Langhorne first recorded alongside Dylan during the sessions for The Freewheelin' Bob Dylan's "Corrina, Corrina" and Dylan's first single "Mixed Up Confusion." He would later play a critical role on 1965's Bringing It All Back Home, where he served as lead guitarist on tracks like "Subterranean Homesick Blues," "Maggie's Farm" and "Outlaw Blues" and provided the notable countermelody to "Mr. Tambourine Man."

"If you had Bruce playing with you, that's all you would need to do just about anything," Dylan wrote in his autobiography Chronicles Volume One.

Langhorne is also credited with inspiring Dylan to pen the song "Mr. Tambourine Man," a legendary cut in its own right that was transformed into a Number One smash by the Byrds.

"'Mr. Tambourine Man," I think, was inspired by Bruce Langhorne," Dylan recounted in the liner notes to his Biograph box set. "Bruce was playing guitar with me on a bunch of the early records. On one session, [producer] Tom Wilson had asked him to play tambourine. And he had this gigantic tambourine. It was like, really big. It was as big as a wagon-wheel. He was playing, and this vision of him playing this tambourine just stuck in my mind. He was one of those characters ... he was like that. I don't know if I've ever told him that."

In addition to his work with Dylan – which included Dylan's 1973 soundtrack for Pat Garrett & Billy the Kid – Langhorne also recorded with Joan Baez, Judy Collins, Richie Havens, Gordon Lightfoot, Tom Rush, Richard & Mimi Fariña and many more.

As the New York Times notes, Langhorne also performed alongside folk legend Odetta at the 1963 March on Washington, playing moments before Martin Luther King, Jr. delivered his "I Have a Dream" speech.